Medikine will use SBIR funding to develop a new technology that will greatly accelerate the discovery of peptide agonists of cytokine receptors, and will make possible the re-engineering of these newly discovered agonists to exhibit novel and medically-valuable bioactivity profiles. This technology will enable the sorting of enormous libraries of stochastically-produced peptides to directly identify those with appropriate receptor- activating properties. This is an important advance beyond the current state-of-the-art in peptide agonist discovery methods that rely on screening for binding to a target receptor, followed by hit confirmation, peptide re-synthesis, and testing for agonist activity one compound at a time. In contrast, Medikine proposes to develop a high throughput method of screening large collections of peptides for functional properties, not simply for binding. This will be accomplished by creating libraries of peptide producing bacteria engineered to express the peptides in a form suitable for direct testing for cytokine receptor activation in ultra-high-throughput formats. The resulting functional assays are designed to identify peptides with new cytokine-like properties useful for many therapeutic applications in diabetes, obesity, fibrosis, cancer, and immunotherapy. In Phase I studies, a suitable strain of peptide-producing bacteria will be constructed, and performance of the peptide in a cytokine receptor activation assay will be assessed. Achievement of Phase I objectives will provide the groundwork for a Phase II SBIR program to develop a high-throughput, well-free technology to screen the activity of large peptide libraries; and to utilize this method for the discovery of peptides that faithfully mimic te activities of natural cytokines. Specific goals of Phase II will include development of protocols t screen large peptide collections for novel cytokine receptor agonists, and methods of selecting peptides that induce novel patterns of signal transduction activation leading to new and useful cytokine-like bioactivities.